This career development award will provide the necessary training and resources for Dr. Cheryl L. Thompson, junior faculty in the department of Family Medicine at Case Western Reserve University, to transition into an independent investigator. Training in the area of structural equation modeling, molecular genetics and breast cancer, through coursework, seminars, conference attendance and project involvement, as directed by her mentors, will allow Dr. Thompson to become a strong breast cancer genetic epidemiologist. High mammographic breast density (MD) is emerging as one of the strongest risk factors, as well as a potential intermediate marker, for breast cancer. Genetic influence clearly plays an important role in breast cancer and is an important determinant of MD. Results from multiple trials showing an unexpected significantly elevated risk of breast cancer among women taking combined hormone replacement therapy (HRT) highlights the important, but under-appreciated, role of progesterone as well as estrogen in the etiology of breast cancer. Perturbation of phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT) signaling has also been implicated as an important oncogenic pathway in breast cancer development. Furthermore, mechanistic studies indicate that cross-talks occur between the estrogen receptor (ER) and progesterone receptor (PR) and PI3K/AKT in breast tissue. Genetic variations in ER/PR and the PI3K/AKT signaling pathway are likely to affect MD, its changes over time, and subsequently, the risk of breast cancer. An ongoing case-control study is recruiting women with a history of breast cancer as well as healthy screened controls. Multiple (^3) screening films prior to the diagnosis of cancer (cases), or prior to recruitment (controls), from 1500 breast cancer cases and 1500 controls are being retrieved to examine the relationship of longitudinal changes in MD and risk of breast cancer. The current proposal expands on this ongoing study to collect genetic samples and examine inherited variants in the ER/PR and PI3K/AKT signaling pathways in relation to both MD and longitudinal changes in MD as they relate to breast cancer risk. An understanding of the effect of inherited polymorphisms in these genes on MD and breast cancer risk will give us important new insight into breast cancer tumorigenesis. Knowledge of these variations as they relate to risk of breast cancer may have significant implication for better risk stratification and prediction and tailored strategies for breast cancer prevention and intervention. This study will provide the platform for the Pi's career development with a focus on breast cancer genetic epidemiology and pathway-based analysis. It will set the stage for the Pi's transition into an independent investigator and for seeking additional national funding based on this project to expand the study population to give sufficient power to tackle the complex gene- gene and gene-environment interactive and joint effects within these pathways on the trajectories of MD and risk of breast cancer.